Division of Gastroenterology, Duke University, Durham, North Carolina 27710, USA.
Drug Saf. 2010 Jun 1;33(6):503-22. doi: 10.2165/11535340-000000000-00000.
Challenges exist in the clinical diagnosis of drug-induced liver injury (DILI) and in obtaining information on hepatotoxicity in humans.
(i) To develop a unified list that combines drugs incriminated in well vetted or adjudicated DILI cases from many recognized sources and drugs that have been subjected to serious regulatory actions due to hepatotoxicity; and (ii) to supplement the drug list with data on reporting frequencies of liver events in the WHO individual case safety report database (VigiBase).
(i) Drugs identified as causes of DILI at three major DILI registries; (ii) drugs identified as causes of drug-induced acute liver failure (ALF) in six different data sources, including major ALF registries and previously published ALF studies; and (iii) drugs identified as being subjected to serious governmental regulatory actions due to their hepatotoxicity in Europe or the US were collected. The reporting frequency of adverse events was determined using VigiBase, computed as Empirical Bayes Geometric Mean (EBGM) with 90% confidence interval for two customized terms, 'overall liver injury' and 'ALF'. EBGM of >or=2 was considered a disproportional increase in reporting frequency. The identified drugs were then characterized in terms of regional divergence, published case reports, serious regulatory actions, and reporting frequency of 'overall liver injury' and 'ALF' calculated from VigiBase.
After excluding herbs, supplements and alternative medicines, a total of 385 individual drugs were identified; 319 drugs were identified in the three DILI registries, 107 from the six ALF registries (or studies) and 47 drugs that were subjected to suspension or withdrawal in the US or Europe due to their hepatotoxicity. The identified drugs varied significantly between Spain, the US and Sweden. Of the 319 drugs identified in the DILI registries of adjudicated cases, 93.4% were found in published case reports, 1.9% were suspended or withdrawn due to hepatotoxicity and 25.7% were also identified in the ALF registries/studies. In VigiBase, 30.4% of the 319 drugs were associated with disproportionally higher reporting frequency of 'overall liver injury' and 83.1% were associated with at least one reported case of ALF.
This newly developed list of drugs associated with hepatotoxicity and the multifaceted analysis on hepatotoxicity will aid in causality assessment and clinical diagnosis of DILI and will provide a basis for further characterization of hepatotoxicity.
药物性肝损伤（DILI）的临床诊断存在挑战，并且难以获取人体肝毒性相关信息。
（i） 建立一个综合清单，其中包括多个公认来源中经充分验证或裁定的 DILI 病例中涉及的药物，以及因肝毒性而受到严重监管行动的药物；（ii） 用世界卫生组织个体病例安全报告数据库（VigiBase）中肝脏事件报告频率的数据补充药物清单。
（i） 从三个主要的 DILI 注册中心确定的导致 DILI 的药物；（ii） 从六个不同数据源（包括主要的 ALF 注册中心和以前发表的 ALF 研究）确定的导致药物性急性肝衰竭（ALF）的药物；（iii） 收集因肝毒性在欧洲或美国受到严重政府监管行动的药物。使用 VigiBase 确定不良事件的报告频率，计算为两个自定义术语“总体肝损伤”和“ALF”的经验贝叶斯几何均值（EBGM），置信区间为 90%。报告频率>或=2 被认为是报告频率的不成比例增加。然后根据区域差异、已发表的病例报告、严重监管行动以及从 VigiBase 计算的“总体肝损伤”和“ALF”的报告频率对确定的药物进行特征描述。
排除草药、补充剂和替代药物后，共确定了 385 种单药；在三个 DILI 注册中心中确定了 319 种药物，在六个 ALF 注册中心（或研究）中确定了 107 种药物，在美国或欧洲因肝毒性而暂停或撤回了 47 种药物。在西班牙、美国和瑞典之间，确定的药物差异显著。在经裁定的案例 DILI 注册中心确定的 319 种药物中，93.4%在已发表的病例报告中发现，1.9%因肝毒性而暂停或撤回，25.7%也在 ALF 注册中心/研究中发现。在 VigiBase 中，319 种药物中的 30.4%与“总体肝损伤”的报告频率不成比例地升高有关，83.1%与至少一个报告的 ALF 病例有关。
新开发的与肝毒性相关的药物清单以及对肝毒性的多方面分析将有助于 DILI 的因果关系评估和临床诊断，并为进一步表征肝毒性提供基础。
